US5621099A - Synthetic method of hymenialdisine and its derivatives and their synthetic intermediates, and those synthetic intermediates - Google Patents

Synthetic method of hymenialdisine and its derivatives and their synthetic intermediates, and those synthetic intermediates Download PDF

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US5621099A
US5621099A US08/586,638 US58663896A US5621099A US 5621099 A US5621099 A US 5621099A US 58663896 A US58663896 A US 58663896A US 5621099 A US5621099 A US 5621099A
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Hirokazu Annoura
Toshio Tatsuoka
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Asubio Pharma Co Ltd
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Suntory Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring

Definitions

  • the present invention relates to a process of producing of hymenialdisine, its derivatives, and their salts of the formula (I): ##STR2## (wherein X 1 is a halogen atom or hydrogen atom.)
  • the present invention further relates to intermediates for producing the above compound (I) and processes for producing the same.
  • hymenialdisine has been isolated from Axinella verrucosa, Acanthella aurantiaca (Cimino, G. et al: Tetrahedron Lett., 23, 767 (1982)), Hymeniacidon aldis (Kitagawa, I. et al: Chem. Pharm. Bull., 31, 2321 (1983)), and an unconfirmed Kololevu sponge (Schmitz, F. et al: J. Nat. Prod., 48, 47 (1985)), while debromohymenialdisine has been isolated from Phakellia flabellata (Sharma, G. et al: J. Chem. Soc., Chem.
  • the compound having an X 1 of a bromine atom is hymenialdisine, while the compound having an X 1 of a hydrogen atom is debromohymenialdisine.
  • Hymenialdisine and debromohymenialdisine are known to have antineoplastic activities (Pettit, G. et al: Can. J. Chem., 68, 1621 (1990)). Furthermore, debromohymenialdisine is known to have ⁇ -adrenoceptor blocking effect (Kobayashi, J. et al: Experimentia., 44, 86 (1988)).
  • hymenialdisine and debromohymenialdisine have an inhibitory action against protein phosphokinases, in particular, protein kinase C (Nishizuka, Y.: Nature, 334, 661 (1988); idem, JAMA, 262, 1826 (1989)), which plays an important role in cellular signal transduction (Nambi, P. et al: International Disclosure W093/16703).
  • protein kinase C for example, cerebral ischemic disorders, cerebral vasospasm, ischemic cardiac diseases, high blood pressure, arteriosclerosis, inflammation, asthma, kidney disorders, rheumatoid arthritus, and sthenia of immunofunctions.
  • Hymenialdisine and debromohymenialdisine can only be obtained in minute quantities when extracted and isolated from nature, so there has been a strong demand for the development of an efficient process of production enabling economical mass production of hymenialdisine and its derivatives.
  • Such a technique has not yet been known. There has just been a few studies on conversion from aldisin. Even these have not given satisfactory results. Complete synthesis is not yet achieved (Prager, R. et al: Aust. J. Chem., 43, 367 (1990); idem, ibid. 45, 1771 (1992)).
  • the objective of the present invention is to provide a process for economically and efficiently producing of hymenialdisine and its derivatives at a mass production.
  • the other objectives of the present invention are to provide synthetic intermediates useful for the production of these compounds and a process for producting the same.
  • the present inventors succeeded in the complete chemical synthesis of hymenialdisine and its derivatives having the formula (I): ##STR3## (wherein X 1 is a halogen atom or hydrogen atom.)
  • halogen atom includes a chlorine atom, bromine atom, and iodine atom.
  • the hymenialdisine having the formula (I) and its derivatives can be synthesized by the processes shown below. These processes will be explained one after the other.
  • the compounds (IIa) and (IIb) are obtained from the known starting materials (VIII) and (XV), then the compound (IV) is obtained from these compounds (II) (step 3).
  • the compound (V) is obtained from the compound (IV) (step 4)
  • the compound (VIa) is obtained from the compound (V) (step 5).
  • the compound (VIb) is obtained from the compound (IVa) (step 6) and the compound (VII) is obtained from the compound (VI) (step 7).
  • the desired compound (I) is obtained from the resultant compound (VII) (step 8).
  • the compound (IIa) having an X 1 in formula (II) of a halogen atom can be synthesized from the known starting material pyrrole-2-carboxylic acid or its derivatives (VIII) by the following steps: ##STR4## (wherein R" is a hydrogen atom or a protective group of a carboxyl group, R 2 is a trimethylsilylethoxymethyl group, benzyloxymethyl group, p-methoxybenzyloxymethyl group, methoxymethyl group, methoxyethoxymethyl group, tert-butoxymethyl group, p-anisyloxymethyl group, guaiacolmethyl group, tert-butyldimethylsiloxymethyl group, dimethyltexylsiloxymethyl group, or tert-butyldiphenylsiloxymethyl group, R 3 is a trimethylsilylethoxymethyl group, benzyloxymethyl group, p-methoxybenzyloxymethyl group, tert-
  • the groups which can be easily replaced by an amino group for the group W of the compound (VIII) include a halogen atom, carboxylic acid residue, etc.
  • the various methods described in the "Compendium for Organic Synthesis” can be used.
  • DEPC diethyl phosphate cyanide
  • DPPA diphenyl phosphate azide
  • DCC dicyclohexylcarbodiimide
  • 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride 2-iodo-1-methylpyridinium iod
  • a method for converting 2-pyrrolecarboxylic acid by an ordinary method to an acid halide, a symmetric acid anhydride, a mixed acid anhydride, a p-nitrophenyl ester, or other active ester, followed by causing a reaction, etc. may be used.
  • the resultant compound (X) is converted to (XI) by a halogenation reaction.
  • This halogenation reaction may be performed by treating the compound (X) in an inert solvent such as methylene chloride, 1,2-dichloroethane, chloroform, acetonitrile, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, or dimethylformamide at a temperature of -50° to 100° C., preferably -10° to 60° C.
  • a halogenation agent such as N-chlorosuccinimide, trichloroisocyanuric acid, tert-butyl hypochlorite, iodine trichloride, N-bromosuccinimide, bromine, dioxane-bromine complex, 2,4,6,6-tetrabromo-2,5-cyclohexadiene, N-iodosuccinimide, iodine, iodine/potassium iodide, iodine/periodic acid, iodine-morpholine complex, iodine monochloride, or iodine monochloride/zinc chloride for 1 to 12 hours.
  • a halogenation agent such as N-chlorosuccinimide, trichloroisocyanuric acid, tert-butyl hypochlorite, iodine trichloride, N-bromosuccinimide,
  • the resultant compound (XI) is treated, if necessary, by the action of an acid or base or by a suitable means such as catalytic reduction to remove the protective groups, then is subjected to a cyclization reaction.
  • the cyclization reaction is performed by treating the compound (XI) with an organic acid such as methanesulfonic acid or an inorganic acid such as sulfuric acid or polyphosphoric acid or by a mixture thereof with phosphorus pentaoxide at room temperature to 170° C., preferably 80° to 130° C.
  • a solvent which is not interfering with the reaction may be added.
  • the resultant compound (XII) may be converted into the compound (XIII) by treatment in an inert solvent such as dimethylformamide, dimethylsulfoxide, tetrahydrofuran, ethylene glycol dimethyl ether, dioxane, benzene, toluene, or xylene in the presence of a base such as sodium hydroxide, potassium hydroxide, or potassium tert-butoxide at a temperature of -50° to 100° C., preferably -20° to 60° C., with 0.8 to 1.5 equivalents, with respect to compound (XII), of trimethylsilylethoxymethyl chloride, benzyloxymethyl chloride, p-methoxybenzyloxymethyl chloride (Kozikowski, A.
  • an inert solvent such as dimethylformamide, dimethylsulfoxide, tetrahydrofuran, ethylene glycol dimethyl ether, dioxane, benzene, toluene, or xylene
  • the resultant compound (XIII) may be converted into the compound (XIV) by treatment in an inert solvent such as dimethylformamide, dimethylsulfoxide, tetrahydrofuran, ethylene glycol dimethyl ether, dioxane, benzene, toluene, or xylene at a temperature of -50° to 100° C., preferably -20° to 60° C., in the presence of a base such as sodium hydroxide, potassium hydroxide, or potassium tert-butoxide, with 0.8 to 1.5 equivalents of trimethylsilylethoxymethyl chloride, benzyloxymethyl chloride, p-methoxybenzyloxymethyl chloride, chloromethylmethyl ether, 2-methoxyethoxymethyl chloride, tert-butoxymethyl chloride, p-anisyloxymethyl chloride, guaiacolmethyl chloride, tert-butyldimethylsiloxymethyl chloride, dimethyltexylsiloxymethyl chloride
  • the resultant compound (XIV) is separated and purified by a purification method generally used, for example, column chromatography, to obtain the compound having the formula (IIa): ##STR5## (wherein R 2 and R 1 are as defined above and X 4 is a halogen atom.)
  • the compounds obtained by these reactions may be used as they are for the next processes, but if necessary, they may also be used after purification by a purification method generally used, for example, recrystallization or column chromatography.
  • the starting aldisin (XV) is a known compound described in Prager, R. et al: Aust. J. Chem., 43, p. 355 to 365 (1990). It may be prepared in the same way as the method for obtaining the compound (XIV) from the compound (XII) of the step 1.
  • the resultant compound (IIb) may be used as is for the next step, but if necessary, it may also be used after purification by a purification method generally used, for example, recrystallization or column chromatography.
  • This step may be performed by causing a reaction in an inert solvent such as tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, benzene, toluene, xylene, or dimethylformamide in the presence of a base such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethylate, or potassium tert-butoxide at a temperature of 0° to 120° C., preferably room temperature to 70° C., with 1 to 10 equivalents, with respect to compound (II), of trimethyl phosphonoacetate, methyldiethyl phosphonoacetate, ethyldimethyl phosphonoacetate, methyldiisopropyl phosphonoacetate, ethyldiethyl phosphonoacetate, isopropyldiethyl phosphonoacetate, tert-butyldiethyl phosphonoacetate, methyl bis(2,2,
  • the compound (IV) obtained by the above method can be used as it is as a material for producing the compound (V), but when necessary it is possible to separate the compound (IVa) used in the step 6 by column chromatography for example, purify it, and then use that.
  • This step may be performed by causing a reaction in an inert solvent such as tetrahydrofuran, diethyl ether, diethylene glycol dimethyl ether, or toluene in the presence of a strong base such as potassium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl) amide, lithium bis(trimethylsilyl)amide, or lithium diisopropylamide, at a temperature of -100° to 20° C., preferably -78° to 0° C., with 1 to 1.5 equivalents, with respect to compound (IV), of an oxidizing agent such as 2-benzenesulfonyl-3-phenyloxaziridine (Davis, F. et al: J. Org.
  • an inert solvent such as tetrahydrofuran, diethyl ether, diethylene glycol dimethyl ether, or toluene
  • a strong base such as potassium bis(trimethylsilyl)amide, sodium bis(trimethyl
  • the compound (V) obtained by the above method may be used as it is as the material for producing the compound (VIa), but if necessary, it may also be used after purification by a purification method generally used, for example, column chromatography.
  • R 4 is an alkylsulfonyloxy group or arylsulfonyloxy group, preferably the alkyl group includes an alkyl group having 1 to 4 carbon atoms or a halogen substituted methyl group, preferably, as the halogen, a fluorine atom or chlorine atom, preferably the aryl group includes a phenyl group p-tolyl group, 4-methoxyphenyl group, 4-chlorophenyl group, or nitrophenyl group.
  • This step may be performed by causing a reaction in an inert solvent such as methylene chloride, 1,2-dichloroethane, chloroform, carbon tetrachloride, acetonitrile, diethyl ether, tetrahydrofuran, dioxane, benzene, toluene, xylene, or ethyl acetate in the presence of a base such as triethylamine, diisopropylethylamine, pyridine, sodium carbonate, sodium hydrogen carbonate, potassium carbonate or potassium hydrogencarbonate at a temperature of -20° to 100° C., preferably -10° to 60° C., with 1 to 10 equivalents, with respect to compound (V), of a sulfonylating agent such as methanesulfonyl chloride, methanesulfonic anhydride, ethanesulfonyl chloride, 1-propanesulfonyl chloride, 1-buta
  • the compound (VIa) obtained by the above method may be used as it is, as the material for producing the compound (VII), but if necessary, it may also be used after purification by a purification method generally used, for example, column chromatography.
  • This step may be performed by treating the compound (IVa) in an inert solvent such as methylene chloride, 1,2-dichloroethane, chloroform, acetonitrile, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, or dimethylformamide at -50° to 120° C., preferably -20° to 80° C., with 0.3 to 1.2 equivalents of a halogenating agent such as N-chlorosuccinimide, trichloroisocyanuric acid, tert-butyl hypochlorite, iodine trichloride, N-bromosuccinimide, bromine, dioxane-bromine complex, 2,4,6,6-tetrabromo-2,5-cyclohexadiene, N-iodosuccinimide, iodine, iodine/potassium iodide, iodine/periodic acid, i
  • the compound (VIb) obtained by the above method may be used as it is, as the material for producing the compound (VII), but if necessary, it may also be used after purification by a purification method generally used, for example, column chromatography.
  • This step may be performed by causing a reaction with the compound (VI) in an inert solvent such as benzene, toluene, xylene, tetrahydrofuran, dioxane, ethylene glycol methyl ether, dimethylformamide, or dimethylsulfoxide at a temperature of 0° to 200° C., preferably room temperature to 120° C., with 1 to 10 equivalents of guanidine for 2 to 24 hours.
  • an inert solvent such as benzene, toluene, xylene, tetrahydrofuran, dioxane, ethylene glycol methyl ether, dimethylformamide, or dimethylsulfoxide
  • the compound (VII) obtained by the above method may be used as it is, as the material for producing the compound (I), but if necessary it may also be used after purification by a purification method generally used, for example, recrystallization or column chromatography.
  • the Z-configuration was confirmed, for example, from the fact that the signal of the 5-position methylene proton in proton NMR shifts to the low magnetic field side due to anisotropic effect of the spatially close carbonyl group. Further, this result can be confirmed from the conversion of the compound (VII) to the compound (I).
  • This step may be performed by causing a reaction at a temperature of -50° to 150° C., preferably -20° to 120° C., of the compound (VII) with 1 to 10 equivalents of tetrabutylammonium fluoride/tetrahydrofuran, 1 to 10 equivalents of tetrabutylammonium fluoride/ethylenediamine, 1 to 10 equivalents of methanol/hydrochloric acid, 1 to 10 equivalents of ethanol/hydrochloric acid, etc.
  • this step may be performed by general deprotection methods such as a method of using an acid catalyst, the catalytic reduction method, and oxidation, for example, the various methods as described in "Protective Groups in Organic Synthesis” (T. W. Greene; John Wiley & Sons), etc.
  • the compound (I) obtained by the above method may be purified by a purification method generally used, for example, recrystallization or column chromatography.
  • an acid addition salt of the compound having the formula (I) may be produced by reacting the same by an ordinary method with an inorganic acid such as hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, or phosphoric acid or an organic acid such as maleic acid, fumaric acid, tartaric acid, citric acid, lactic acid, oxalic acid, acetic acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid, adipic acid, palmitic acid, and tannic acid.
  • an inorganic acid such as hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, or phosphoric acid
  • an organic acid such as maleic acid, fumaric acid, tartaric acid, citric acid, lactic acid, oxalic acid, acetic acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid, adipic acid
  • a 5 g amount of the mixture of the compounds (4) synthesized in Reference Example 4 was gradually added under ice cooling to a 100 ml dimethylformamide suspension of 0.87 g of sodium hydride (60% oil). The mixture was stirred at room temperature for 1 hour. A 3.7 ml amount of trimethylsilylethoxymethyl chloride was dropwise added under ice cooling, the mixture was stirred at room temperature for 2 hours, then a saturated aqueous solution of ammonium chloride was added and extraction was performed by ethyl acetate.
  • a 5 ml dimethylformamide solution of 740 mg of the compound (5) synthesized in Reference Example 5 was dropwise added under ice cooling to a 10 ml dimethylformamide suspension of 87.3 mg of sodium hydride (60% oil). The mixture was stirred at room temperature for 1 hour. A 0.39 ml amount of trimethylsilylethoxymethyl chloride was dropwise added under ice cooling, the mixture was stirred at room temperature for 2 hours, then a saturated aqueous solution of ammonium chloride was added and extraction was performed by ethyl acetate.
  • Example 2 The same procedure was followed as in Example 1 to obtain 205 mg of the above-referenced compound (11) (yield 25%) and 470 mg of the above-referenced compound (12) (yield 58%) from 700 mg of the compound (8) synthesized in Reference Example 7, 329 mg of sodium hydride (60% oil), and 1.63 ml of ethyl diethyl phosphonoacetate.
  • a 135 mg amount of the above-referenced compound (14) (yield 72%) was obtained from 182 mg of a mixture of the compound (11) and (12) synthesized in Example 2, 0.88 ml of potassium bis(trimethylsilyl)amide (0.5 mol/toluene solution), and 106 mg of 2-benzenesulfonyl-3-phenoyloxaziridine, in the same manner as in Example 3.
  • a 940 mg amount of the above-referenced compound (16) (yield 97%) was obtained from 840 mg of the compound (14) synthesized in Example 4, 0.69 mgl of triethylamine, and 0.15 ml of methanesulfonyl chloride, in the same manner as in Example 5.
  • a 420 mg amount of the above-referenced compound (19) was obtained from 935 mg of the compound (16) synthesized in Example 6 and 281 mg of guanidine to obtain the crude crystals in the same manner as in Example 8 followed by, recrystallizing from ether/methanol (yield 50%).

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US08/586,638 1994-05-18 1995-05-17 Synthetic method of hymenialdisine and its derivatives and their synthetic intermediates, and those synthetic intermediates Expired - Fee Related US5621099A (en)

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JP10403094A JP3714685B2 (ja) 1994-05-18 1994-05-18 ハイメニアルディシン及びその誘導体並びにそれらの合成中間体の製造法並びにその合成中間体
PCT/JP1995/000941 WO1995031462A1 (fr) 1994-05-18 1995-05-17 Hymenialdisine et derive de celle-ci, procede pour produire un intermediaire servant a synthetiser ce compose, et cet intermediaire

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US5962448A (en) * 1995-12-01 1999-10-05 Suntory Limited Pyrroloazepine derivatives
US6103899A (en) * 1993-04-08 2000-08-15 The Trustees Of Columbia University In The City Of New York Bicyclic aminoimidazoles
US6197954B1 (en) 1998-01-30 2001-03-06 The Trustees Of Columbia University In The City Of New York Intermediates for the synthesis of debromohymenialdisine and processes thereof
US6211361B1 (en) * 1999-07-20 2001-04-03 State Of Oregon Acting By And Through The Oregon State Board Of Higher Education On Behalf Of Oregon, State Univeristy Method for making debromohymenialdisine and analogs thereof
EP1106180A1 (fr) * 1999-12-08 2001-06-13 Centre National De La Recherche Scientifique (Cnrs) Utilisation de l'hymenialdisine et de ses dérivés pour la fabrication de médicaments
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US20040235820A1 (en) * 2003-05-19 2004-11-25 Board Of Trustees Of Michigan State University Preparation of hymenialdisine derivatives and use thereof
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DE69522642T2 (de) 2002-04-18
EP0711773A4 (fr) 1996-06-19
EP0711773B1 (fr) 2001-09-12
DE69522642D1 (de) 2001-10-18
AU2454195A (en) 1995-12-05
CA2167515A1 (fr) 1995-11-23
AU701436B2 (en) 1999-01-28
JP3714685B2 (ja) 2005-11-09
KR960703916A (ko) 1996-08-31
EP0711773A1 (fr) 1996-05-15
WO1995031462A1 (fr) 1995-11-23
ES2160164T3 (es) 2001-11-01

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